The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens ("HLA"), or major histocompatibility complexes ("MHCs"), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See Male et al., Advanced Immunology (J.P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cell and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See Barinaga, Science, 257: 880 (1992); Fremont et al., Science, 257: 919 (1992); Matsumura et al., Science, 257: 927 (1992); and Latron et al., Science, 257: 964 (1992).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs. The genes are said to code for "tumor rejection antigen precursors" or "TRAP" molecules, and the peptides derived therefrom are referred to as "tumor rejection antigens" or "TRAs". See Traversari et al., Immunogenetics, 35: 145 (1992); van der Bruggen et al., Science, 254: 1643 (1991), for further information on this family of genes. Also, see U.S. Pat. No. 5,342,774.
In U.S. patent application Ser. No. 938,334, now U.S. Pat. No. 5,405,940 the disclosure of which is incorporated by reference, nonapeptides are taught which are presented by the HLA-A1 molecule. The reference teaches that given the known specificity of particular peptides for particular HLA molecules, a particular peptide is expected to bind one HLA molecule, but not others. This is important, because different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HIA molecule has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype. There is a need for further work in the area, because cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
In U.S. patent application Ser. No. 008,446, filed Jan. 22, 1993 now U.S. Pat. No. 5,629,166 and incorporated herein by reference, it is disclosed that the MAGE-1 expression product is processed to a second TRA. This second TRA is presented by HLA-Cw*1601 molecule. The disclosure shows that a given TRAP can yield a plurality of TRAs.
In U.S. patent application Ser. No. 994,928, filed Dec. 22, 1992, and incorporated by reference herein now abandoned, tyrosinase is described as a tumor rejection antigen precursor. This reference discloses that a molecule which is produced by some normal cells (e.g., melanocytes), is processed in tumor cells to yield a tumor rejection antigen that is presented by HhA-A2 molecules.
In U.S. patent application Ser. No. 08/032,978, filed Mar. 18, 1993 now U.S. Pat. No. 5,620,886, and incorporated herein by reference, a second TRA, not derived from tyrosinase, is taught to be presented by HLA-A2 molecules. The TRA is derived from a TRAP, but is coded for by a non MAGE gene. This disclosure shows that a particular HLA molecule may present TRAs derived from different sources.
In U.S. patent application Ser. No. 08/079,110 filed Jun. 17, 1993 now U.S. Pat. No. 5,571,711, which is incorporated herein by reference, a new family of genes, referred to therein as the BAGE family, is disclosed. It was observed that these genes also code for tumor rejection antigen precursors. It is disclosed in the application that the MHC molecule known as HLA-Cw*1601 presents a tumor rejection antigen derived from a BAGE tumor rejection antigen precursor; however, the tumor rejection antigen was not disclosed. The tumor rejection antigen is disclosed in U.S. patent application Ser. No. 08/196,630 filed Feb. 15, 1994 now U.S. Pat. No. 5,683,886, which is incorporated herein by reference. The application also discloses ramifications stemming from the tumor rejection antigen, as well as therapeutic and diagnostic methods utilizing the antigen.
The present application is directed to isolated nucleic acid molecules which encode BAGE tumor rejection antigen precursors described in patent application Ser. No. 08/196,630 now U.S. Pat. No. 5,683,886. The present application is further directed to therapeutic and diagnostic methods utilizing the isolated BAGE nucleic acid molecule.
The invention is elaborated upon further in the disclosure which follows.